Investigations of HIV-1 pathogenesis have also been hampered by a lack of a tractable animal model: with the exception of one recent report, HIV-1 inoculations of chimpanzees do not result in immunodeficiency. When it became clear that SIV, the close primate lentivirus relative of HIV-1, induced an immunodeficiency in Asian macaques with clinical features similar to AIDS in man, SIV/HIV chimeric viruses (SHIVs) were constructed to address pathogenicity and vaccine issues related to the incorporated HIV- 1 sequences. Compared to SIV, however, many of the first- generation SHIVs did not replicate to high levels in vivo or induce disease. During the past year a pathogenic SHIV virus containing the HIV-1 tat, rev, vpu and env genes was constructed. This virus was used to challenge macaques previously immunized with a live attenuated SIV vaccine. Despite having dissimilar Env glycoproteins and, in the absence of detectable neutralizing antibodies, the vaccinated macaques were protected from a subsequent infection with a SHIV virus. In a separate group of experiments, the role of CD8 T lymphocytes in resolving primary lentiviral infections was studies by administering mouse-anti- human CD8 monoclonal antibodies (mAb) at the time of the acute SHIV infection. Animals treated with such antibody failed to clear the virus promptly, exhibited 100-fold higher peak virus load, and sustained greater depletion of CD4 T lymphocytes.